Matthias C. WitschelMatthias RottmannAnatol SchwabUbolsree LeartsakulpanichPenchit ChitnumsubMichael SeetSandro TonazziGeoffrey SchwertzFrank StelzerThomas MietznerCase McNamaraFrank ThaterCéline FreymondAritsara JaruwatChatchadaporn PinthongPinpunya RiangrungrojMouhssin OufirMatthias HamburgerPascal MäserLaura M. Sanz-AlonsoSusan CharmanSergio WittlinYongyuth YuthavongPimchai ChaiyenFrançois DiederichBASF SESwiss Tropical and Public Health Institute (Swiss TPH)Universitat BaselETH ZurichThailand National Center for Genetic Engineering and BiotechnologyCalifornia Institute for Biomedical ResearchMahidol UniversityGlaxoSmithKline plc, SpainMonash Institute of Pharmaceutical Sciences2018-11-232018-11-232015-04-09Journal of Medicinal Chemistry. Vol.58, No.7 (2015), 3117-313015204804002226232-s2.0-84927603340https://repository.li.mahidol.ac.th/handle/20.500.14594/35469© 2015 American Chemical Society. Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1021/jm501987h